Tira Jing Ying Tan

Triple-Negative Breast Cancer: Clinical Features

Triple-negative breast cancers (TNBCs) lack expression of the three prognostic and predictive biomarkers routinely used in clinical management. It is a heterogeneous disease and clinically has aggressive tumor biology with the worst disease-specific outcomes as compared to other breast cancer subtypes. The clinical management of TNBC represents an important challenge, and limited treatment strategies are an unmet clinical need. These cancers do not respond to endocrine agents or targeted agents. Chemotherapy is the mainstay of treatment. This chapter describes the epidemiology, risk factors, clinical features, natural history, and prognosis of TNBC.

Abstract B22: Inducing cell state transitions in triple-negative breast cancer (TNBC)

Triple-negative breast cancer (TNBC), as immunohistochemically defined by its estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor-2 (HER2)-negative status, is an important subtype due to its biologically aggressive behavior and limited treatment options available. TNBC is associated with an overall poorer prognosis, with higher risk of disease recurrence/progression and shorter duration of treatment response, i.e., treatment resistance. Treatment resistance may be largely attributed to cancer stem cells (CSCs), which are intrinsically treatment resistant and continually self-renew, proliferate, and differentiate into different phenotypes. Activation of the cell biologic program, epithelial-mesenchymal transition (EMT), has been demonstrated to promote the dedifferentiation of heterogeneous subpopulations of cancer cells towards CSC phenotypes. We hypothesized that induction of the mesenchymal-epithelial transition (MET) program might disrupt CSC function, drive differentiation, and render greater susceptibility to conventional chemotherapy. In this study, we utilized high-throughput chemical-genetic screens to uncover a potent class of MET mediators. With the use of in vitro and in vivo models of TNBC, we showed that changing the malignant cell state to a differentiated phenotype by inducing MET reduced mammosphere formation, increased chemosensitivity, and decreased the tumor burden in NSG mice. Delving into the mechanisms of tumor differentiation via ChIP-seq, RNA-seq, and Gene Ontology analysis revealed differences in metabolic status between cell states, which might be exploited in the treatment of TNBC. We also assessed combinations of MET mediators, in order to increase the potency and durability of differentiation. Hence, this study assessed the role of differentiation in the treatment of TNBC and the efficacy of various MET mediators, singly and in combination, in inducing differentiation. Citation Format: Ser Yue Loo, Liping Toh, Elina Pathak, Wilson Tan, Siming Ma, Ju Yuan, Giridharan Periyasamy, Federico Torta, Jack Chan, Tira Tan, Yi Rong Sim, Veronique Tan, Benita Tan, Preetha Madhukumar, Wei Sean Yong, Kong Wee Ong, Chow Yin Wong, Markus R. Wenk, Roger Foo, Yoon-Sim Yap, Elaine Lim, Wai Leong Tam. Inducing cell state transitions in triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B22.

Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018?

The working immunohistochemical definition of triple-negative breast cancer (TNBC) is admittedly reductionist and has only limited usefulness for informing oncologists about therapeutic decisions beyond chemotherapy. Early molecular taxonomies of TNBC based heavily on gene expression profiling, which is not readily available in the clinic today, do not necessarily encompass other molecular targets already incorporated into rationally designed clinical trials. We state that it is possible to delineate five subgroups of TNBC relevant to present-day clinical practice and cover the evidence that lends credence to emerging biomarker-directed treatment strategies for each subgroup.

First-in-man study of Ad-sig-hMUC1/ecdCD40L vaccine for immunotherapy of MUC1 overexpressing epithelial cancers.

3098Background: Ad-sig-hMUC1/ecdCD40L vaccine is an adenoviral vector encoding the human MUC-1 epithelial antigen bound to an immune stimulant, the extracellular domain of the CD40 ligand (CD40L) a...